The molecular mechanism of neurodegeneration in transmissible spongiform encephalopathies remains uncertain. In this study, it was demonstrated that prion-infected hypothalamic neuronal GT1 cells displayed a higher sensitivity to induced oxidative stress over noninfected cells. In addition, the infected cells presented an increased lipid peroxidation and signs of apoptosis associated with a dramatic reduction in the activities of the glutathione-dependent and superoxide dismutase antioxidant systems. This study indicates for the first time that prion infection results in an alteration of the molecular mechanisms promoting cellular resistance to reactive oxygen species. This finding is vital for future therapeutic approaches in transmissible spongiform encephalopathies and the understanding of the function of the prion protein.

The N-terminal region of the prion protein PrP^C contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrP^C has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrP^C itself. However, up to now the link between PrP^C expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrP^C, copper binding, and resistance to oxidative stress. Radioactive copper (⁶⁴Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrP^C expression in a cell line expressing a doxycycline-inducible murine PrP^C gene. Cellular PIPLC pretreatment indicated that PrP^C was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrP^C expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.

The trace element selenium is an essential micronutrient that has received considerable attention for its potential use in the prevention of cancer. In spite of this interest, the mechanism(s) by which selenium might function as a chemopreventive remain to be determined. Considerable experimental evidence indicates that one possible mechanism by which selenium supplementation may exert its benefits is by enhancing the DNA damage repair response, and this includes data obtained using cultured cells, animal models as well as in human clinical studies. In these studies, selenium supplementation has been shown to be beneficial in reducing the frequency of DNA adducts and chromosome breaks, consequentially reducing the likelihood of detrimental mutations that ultimately contribute to carcinogenesis. The benefits of selenium can be envisioned as being due, at least in part, to it being a critical constituent of selenoproteins such as glutathione peroxidases and thioredoxin reductases, proteins that play important roles in antioxidant defence and maintaining the cellular reducing environment. Selenium, therefore, may be protective by preventing DNA damage from occurring as well as by increasing the activity of repair enzymes such as DNA glycosylases and DNA damage repair pathways that involve p53, BRCA1 and Gadd45. An improved understanding of the mechanism of selenium’s impact on DNA repair processes may help to resolve the apparently contradicting data obtained from decades of animal work, human epidemiology and more recently, clinical supplementation studies.

26RFa is a novel RFamide peptide originally isolated in the amphibian brain. The 26RFa precursor has been subsequently characterized in various mammalian species but, until now, the anatomical distribution and the molecular forms of 26RFa produced in the CNS of mammals, in particular in human, are unknown. In the present study, we have investigated the localization and the biochemical characteristics of 26RFa‐like immunoreactivity (LI) in two regions of the human CNS – the hypothalamus and the spinal cord. Immunohistochemical labeling using specific antibodies against human 26RFa andin situhybridization histochemistry revealed that in the human hypothalamus 26RFa‐expressing neurons are located in the paraventricular and ventromedial nuclei. In the spinal cord, 26RFa‐expressing neurons were observed in the dorsal and lateral horns. Characterization of 26RFa‐related peptides showed that two distinct molecular forms of 26RFa are present in the human hypothalamus and spinal cord, i.e. 26RFa and an N‐terminally elongated form of 43 amino acids designated 43RFa. These data provide the first evidence that 26RFa and 43RFa are actually produced in the human CNS. The distribution of 26RF‐LI suggests that 26RFa and/or 43RFa may modulate feeding, sexual behavior and transmission of nociceptive stimuli.